Glucagon-like Peptide-1 Suppresses the Proliferation and Migration of Vascular Smooth Muscle Cells: Implications for Preventive Effects on Atherosclerosis

Our group previously demonstrated the suppressive effect of glucagon-like peptide-1 (GLP-1) on macrophage-driven atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. In the present study we investigated the suppressive effect of GLP-1 on the atherogenic phenotype of vascular smooth muscle cells (VSMCs) in vivo using apoE-/- mice, and the proliferation and migration of human VSMCs in vitro. A 4-week infusion of GLP-1 in 17-week-old apoE-/- mice significantly reduced the proliferative VSMC phenotype stained with SMemb. Platelet-derived growth factor (PDGF) -BB significantly stimulated the proliferation of human aortic VSMCs by three fold. Both 0.1 and 1nmol/l GLP-1 significantly suppressed the PDGF-induced VSMC proliferation, and this suppressive effect was significantly abolished by the GLP-1 receptor antagonist exendin (9-39) (50nmol/l). The GLP-1 receptor agonists liraglutide (100nmol/l) and exendin-4 (100nmol/l) mimicked GLP-1, significantly suppressing PDGF-induced VSMC proliferation. PDGF-BB significantly stimulated the migration of human aortic VSMCs by 1.7 -fold, and this effect was significantly suppressed by 1nmol/l GLP-1. These findings suggest that GLP-1-related treatments may prevent the progression of atherosclerotic lesions by suppressing the proliferation and migration of VSMCs, which are characteristic features of atherosclerosis

Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine

Background Non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion. Methodology/Principal Findings A single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion. Conclusions/Significance The present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ

Relationship between Rate of Force Development of Tongue Pressure and Physical Performance

In the assessment of skeletal muscle strength, rate of force development (RFD) is clinically identified as a functional index that reflects the effects of aging, but there are few reports on RFD of the tongue. The purpose of this study was to examine the relationship between RFD of tongue pressure (RFD-TP) and oral and whole-body physical performance in older adults, and to clarify its characteristics. We enrolled adults aged ≥65 years with pathological occlusal contact in premolar and molar regions of teeth in the Tamba-Sasayama area, Japan, from 2017 to 2018. Maximum tongue pressure (MTP) and the speed to reach the maximum tongue pressure (RFD-TP) were evaluated as measures of tongue function. Oral functions related to objective measures of tongue function, such as repetitive saliva swallowing test, oral diadochokinesis, and physical status or performance, such as mini mental state examination, body mass index, skeletal mass index, knee extension force, one-leg standing time, grip strength, walking speed, timed up-and-go test, and five-time chair stand speed was evaluated. No significant correlation was found between MTP and age, but RFD-TP had a significant negative correlation with age. Neither RFD-TP nor MTP showed a significant correlation with oral function. RFD-TP was associated with physical performance, such as knee extension force and one-leg standing time. RFD-TP is more sensitive to aging than MTP. In addition, RFD-TP is related to physical performance and may be useful for the early detection of frailty

The Relationship between Dietary Habits and Frailty in Rural Japanese Community-Dwelling Older Adults: Cross-Sectional Observation Study Using a Brief Self-Administered Dietary History Questionnaire

To develop effective nutritional interventions for preventing frailty, the specific problems associated with the dietary habits of individuals based on sex differences must be identified. The purpose of this study was to evaluate the association between dietary habits and frailty in rural Japanese community-dwelling older adults. We recruited 800 participants, aged 65 and older, who underwent a comprehensive health examination between November 2015 and December 2017. Dietary habits were assessed by a brief self-administered dietary history questionnaire. Frailty was determined using either the Kihon Checklist (KCL) or the Japanese version of the Cardiovascular Health Study (J-CHS). The percentage of frail older adults was 8.4% according to KCL and 4.0% according to J-CHS. Various kinds of nutrient intakes, including three major nutrients, minerals, and vitamins in frail men, according to KCL, were the lowest. By contrast, there were no differences in nutrient intake between the robust, prefrail, and frail female groups according to KCL. We found significant associations of the intakes of soluble dietary fiber, potassium, folate, and vitamin C with a frail status in men (p = 0.035, 0.023. 0.012, and 0.007, respectively), and an association of the intake of vitamin C with a frail status in women (p = 0.027) according to J-CHS. Attention should be paid to the diagnostic criteria of frailty and to sex differences, when nutritional interventions for the prevention of frailty are planned

Differentiation of BrdU-positive cells in the dentate gyrus in rats 28 days after the subchronic treatment with fluoxetine.

<p>BrdU-positive cells (green) were co-labeled with a neuronal marker, NeuN (A), but not GFAP (B). Scale bars: 400 µm in lower magnification and 40 µm in higher magnification.</p

Mean escape latency in the Morris water maze task.

<p>There was no significant difference between the treatments.</p

Cell proliferation in the SVZ and SGZ.

<p>(<b>A, B</b>) Coronal sections of the SVZ of the lateral ventricle contralateral (A) or ipsilateral (B) to the 6-OHDA lesioning in an animal from the 6-OHDA group. BrdU-positive nuclei are clearly observed. (<b>C, D</b>) Sections of the dentate gyrus of the hippocampus contralateral (C) or ipsilateral (D) to the 6-OHDA lesioning. BrdU-positive cells (arrows) are observed in the SGZ of the dentate gyrus.</p

Reduced TH immunoreactivity in the striatum, midbrain, and hippocampus following 6-OHDA lesioning.

<p>(<b>A, B</b>) Coronal sections of the striatum immunostained for TH in representative animals from the sham group (A) and 6-OHDA group (B). Almost complete loss of TH immunoreactivity is observed in the right striatum (dotted area) of the 6-OHDA group animal. (<b>C, D</b>) Coronal sections of the midbrain immunostained for TH in animals from the sham group (C) and 6-OHDA group (D). (<b>E–H</b>) Sections of the SNc (E, F) and ventral tegmental area (G, H) at higher magnification of C and D. is The 6-OHDA group animal (F, H) has fewer TH-positive dopaminergic cells than the sham-operated animal (E, G). (<b>I–L</b>) Coronal sections of the hippocampus in animals from the sham group (I, K) and 6-OHDA group (J, L). TH-positive fibers are observed in the hilus (h) as well as in the granular cell layer (g) of the dentate gyrus in the sham group animal (I, K), which is completely lost in the 6-OHDA lesioned animal (J, L).</p